ABCA1-mediated cholesterol efflux generates microparticles in addition to HDL through processes governed by membrane rigidity.
ATP-binding cassette transporter A1 (ABCA1) mediates cholesterol efflux to lipid-poor apolipoprotein A-I (apoA-I) and generates HDL. Here, we demonstrate that ABCA1 also directly mediates the production of apoA-I free microparticles. In baby hamster kidney (BHK) cells and RAW macrophages, ABCA1 expression led to lipid efflux in the absence of apoA-I and released large microparticles devoid of apoB and apoE. We provide evidence that these microparticles are an integral component of the classical cholesterol efflux pathway when apoA-I is present and accounted for approximately 30% of the total cholesterol released to the medium. Furthermore, microparticle release required similar ABCA1 activities as was required for HDL production. For instance, a nucleotide binding domain mutation in ABCA1 (A937V) that impaired HDL generation also abolished microparticle release. Similarly, inhibition of protein kinase A (PKA) prevented the release of both types of particles. Interestingly, physical modulation of membrane dynamics affected HDL and microparticle production, rigidifying the plasma membrane with wheat germ agglutinin inhibited HDL and microparticle release, whereas increasing the fluidity promoted the production of these particles. Given the established role of ABCA1 in expending nonraft or more fluid-like membrane domains, our results suggest that both HDL and microparticle release is favored by a more fluid plasma membrane. We speculate that ABCA1 enhances the dynamic movement of the plasma membrane, which is required for apoA-I lipidation and microparticle formation.
Nandi
Shilpi
S
Ottawa Health Research Institute and Department of Biochemistry, Microbiology & Immunology, University of Ottawa, Ottawa, Ontario K1Y 4E9, Canada.
Ma
Loretta
L
Ottawa Health Research Institute and Department of Biochemistry, Microbiology & Immunology, University of Ottawa, Ottawa, Ontario K1Y 4E9, Canada.
Denis
Maxime
M
Ottawa Health Research Institute and Department of Biochemistry, Microbiology & Immunology, University of Ottawa, Ottawa, Ontario K1Y 4E9, Canada.
Karwatsky
Joel
J
Ottawa Health Research Institute and Department of Biochemistry, Microbiology & Immunology, University of Ottawa, Ottawa, Ontario K1Y 4E9, Canada.
Li
Zhiqiang
Z
SUNY Downstate Medical Center, Brooklyn, NY 11203.
Jiang
Xian-Cheng
XC
SUNY Downstate Medical Center, Brooklyn, NY 11203.
Zha
Xiaohui
X
Ottawa Health Research Institute and Department of Biochemistry, Microbiology & Immunology, University of Ottawa, Ottawa, Ontario K1Y 4E9, Canada. Electronic address: xzha@ohri.ca.
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D016632:Apolipoprotein A-I / Q000378:metabolism; D001693:Biological Transport, Active / Q000187:drug effects; D002460:Cell Line; D055252:Cell-Derived Microparticles / Q000187:drug effects / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism*; D006224:Cricetinae; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008075:Lipoproteins, HDL / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008560:Membrane Fluidity / Q000187:drug effects / Q000502:physiology; D051379:Mice; D015735:Mifepristone / Q000494:pharmacology; D011994:Recombinant Proteins / Q000378:metabolism; D014909:Wheat Germ Agglutinins / Q000494:pharmacology
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D008070:Lipopolysaccharides; D008075:Lipoproteins, HDL; D011994:Recombinant Proteins; D014909:Wheat Germ Agglutinins; D015735:Mifepristone; D002784:Cholesterol; D017868:Cyclic AMP-Dependent Protein Kinases